Homozygous sickle cell disease, known also as sickle cell anemia (SCA), results from inheritance of the sickle cell betas-globin gene from both parents and is characterized usually by marked clinical severity. Some children with sickle cell disease have delayed growth and sexual development. The reason for the delayed growth and associated poor weight gain is not well understood but it might be associated with the increased requirement for protein and energy. The underlying physiological mechanism of this increase, in addition to chronic anemia, could be explained in part by the accelerated synthesis of new red blood cells and the altered catabolism of sickled red blood cells. However, how these metabolic events develop and progress during the accelerated growth in SCA adolescents is unknown. The central hypothesis of this application is that increased whole-body protein turnover diverts protein from normal growth pathways in SCA adolescents. The rationale for the proposed research is that quantifying protein needs and finding the underlying mechanism(s) for stunting will lead us to establishing nutritional recommendations and designing specific supplementation for SCA children and adolescents. The specific aims are: 1) to determine how much protein is needed in growing SCA adolescents using breakpoint analysis of variables derived from 24-h leucine oxidation and balance, whole body protein turnover, and nitrogen balance, and 2) to determine how much protein requirements are changing during pubertal growth in adolescents with SCA. In the proposed longitudinal study of SCA adolescents, protein requirements will be established using stable isotope tracer techniques, body composition assessment, and indirect calorimetry. Healthy adolescents matched initially for Tanner stage of sexual development, sex, and ethnicity will serve as controls in these experiments. The proposed research is significant, because it is expected to result in new guidelines for nutritional management of adolescents with SCA that will significantly improve their growth rate and attendant weight gains. In addition, we will explain how growth rate in SCA adolescents is altered by increased demands for energy caused by higher whole-body protein turnover and chronic hemolytic anemia. Finally, what is learned from this research will contribute to broader understanding of how SCA affects protein and energy metabolism, how these changes alter growth in SCA adolescents, and what underlying physiological mechanism(s) are involved.